Molecular mechanisms underlying the neuroprotection of environmental enrichment in Parkinson's disease.

Parkinson's disease is the most common movement disorder, affecting about 1% of the population over the age of 60 years. Parkinson's disease is characterized clinically by resting tremor, bradykinesia, rigidity and postural instability, as a result of the progressive loss of nigrostriatal dopaminergic neurons. In addition to this neuronal cell loss, Parkinson's disease is characterized by the accumulation of intracellular protein aggregates, Lewy bodies and Lewy neurites, composed primarily of the protein α-synuclein. Although it was first described almost 200 years ago, there are no disease-modifying drugs to treat patients with Parkinson's disease. In addition to conventional therapies, non-pharmacological treatment strategies are under investigation in patients and animal models of neurodegenerative disorders. Among such strategies, environmental enrichment, comprising physical exercise, cognitive stimulus, and social interactions, has been assessed in preclinical models of Parkinson's disease. Environmental enrichment can cause structural and functional changes in the brain and promote neurogenesis and dendritic growth by modifying gene expression, enhancing the expression of neurotrophic factors and modulating neurotransmission. In this review article, we focus on the current knowledge about the molecular mechanisms underlying environmental enrichment neuroprotection in Parkinson's disease, highlighting its influence on the dopaminergic, cholinergic, glutamatergic and GABAergic systems, as well as the involvement of neurotrophic factors. We describe experimental pre-clinical data showing how environmental enrichment can act as a modulator in a neurochemical and behavioral context in different animal models of Parkinson's disease, highlighting the potential of environmental enrichment as an additional strategy in the management and prevention of this complex disease.

Biochemical and behavioral effects of rosmarinic acid treatment in an animal model of Parkinson's disease induced by MPTP.

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. The main therapeutic approach available nowadays relieves motor symptoms but does not prevent or stop neurodegeneration. Rosmarinic acid (RA), an ester of caffeic and 3,4-dihydroxyphenylacetic acids, is obtained from numerous plant species such as Salvia officinalis L. (sage) and Rosmarinus officinalis (rosemary). This compound has a wide spectrum of biological activities, such as antioxidant and anti-inflammatory, and could be an additional therapy for neurodegenerative disorders. Here we evaluated the potential neuroprotective effects of RA treatment in a murine model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Mice were separated into four groups: CN, Control/saline; RA, Rosmarinic acid/vehicle; MPTP, MPTP/saline; MPTP+RA, MPTP/RA. RA (20 mg/kg, or vehicle) was administered orally by intra-gastric gavage for 14 days, one hour before MPTP or saline injection. MPTP groups received the drug (30 mg/kg, intraperitoneally) once a day for five days (fourth to the eighth day of the experiment). MPTP-treated animals displayed hyperlocomotion behavior, which was significantly prevented by RA treatment. In addition, RA treatment increased dopaminergic signaling in the parkinsonian mice and improved the monoaminergic system in healthy animals. Analysis of alterations in the striatal mRNA expression of dopaminergic system components showed that MAO-A expression was increased in the MPTP+AR group. Overall, this study brings new evidence of the potential neuroprotective properties of RA not only in preventing behavioral features observed in PD, but also by improving neurotransmission in the healthy brain.

Behavioral, Biochemical and Molecular Characterization of a Parkinson's Disease Mouse Model Using the Neurotoxin 2'-CH3-MPTP: A Novel Approach.

The neurotoxin MPTP has long been used to create a mouse model of Parkinson's disease (PD). Indeed, several MPTP analogues have been developed, including 2'-CH3-MPTP, which was shown to induce nigrostriatal DA neuronal depletion more potently than MPTP. However, no study on behavioral and molecular alterations in response to 2'-CH3-MPTP has been carried out so far. In the present work, 2'-CH3-MPTP was administered to mice (2.5, 5.0 and 10 mg/kg per injection, once a day, 5 days) and histological, biochemical, molecular and behavioral alterations were evaluated. We show that, despite a dose-dependent-like pattern observed for nigrostriatal dopaminergic neuronal death and dopamine depletion, dose-specific alterations in dopamine metabolism and in the expression of dopaminergic neurotransmission-associated genes could be related to specific motor deficits elicited by the different doses tested. Interestingly, 2'-CH3-MPTP leads to increased DAT and MAO-B transcription, which could explain, respectively, its higher potency and the requirement of higher doses of MAO inhibitors to prevent nigrostriatal neuronal death when compared to MPTP. Also, perturbations in dopamine metabolism as well as possible alterations in dopamine bioavailability in the synaptic cleft were also identified and correlated with strength and ambulation deficits in response to specific doses. Overall, the present work brings new evidence supporting the distinct effects of 2'-CH3-MPTP when compared to its analogue MPTP. Moreover, our data highlight the utmost importance of a precise experimental design, as different administration regimens and doses yield different biochemical, molecular and behavioral alterations, which can be explored to study specific aspects of PD.